Inhibitor-resistant urokinase

Details Inhibitor-resistant urokinase Inhibitor-resistant urokinase

1992-09-08

1997-07-15

Jacobson, Dian C.

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

424 9464, 435 698, 4351723, 800 2, C12N 972, C12N 1555, C12N 1579, A61K 3849

Patent

active

056482531

ABSTRACT:
Mutants of human urokinase are produced which have an altered amino acid sequence in the domain responsible for binding of plasminogen activator inhibitor(s). One example of an inhibitor resistant mutant is described in detail. Six amino acids (179-184), R H R G G S, have been deleted from the mature urokinase. The gene encoding inhibitor resistant preprourokinase is chemically synthesized according to computer-designed nucleotide sequences containing convenient restriction endonuclease cleavage sites, a signal for the initiation of translation, a sequence encoding the signal peptide of mouse whey acid protein and a complete coding sequence for mature inhibitor-resistant urokinase. The gene was used to transform cultured mouse cells to produce clones that stably incorporate the gene in the genome. Clones with high levels of expression were used as the hosts for production of this protein. Alternatively, the DNA for the inhibitor-resistant prourokinase/urokinase, in combination with a tissue specific promoter, could be introduced into fertilized embryos, the embryo implanted into a suitably prepared female of the same species, and the offspring analyzed for presence of the prourokinase/urokinase gene. The transgenic animals can then be bred and the urokinase produced in the milk.

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